An Association Analysis of Gene-Environment Interactions in the PON Region in Late-Onset Sporadic Parkinson's Disease

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Abstract An Association Analysis of Gene-Environment Interactions in the PON Region in Late-Onset Sporadic Parkinson's Disease Nirupama Shridhar Chair of Supervisory Committee: Dr. Karen Edwards Institute for Public Health Genetics (IPHG) Objective: The PON region (7q21.3-7q22), comprising the three PON genes, PON1, PON2, and PON3, has been assessed for its role as a potential gene for risk susceptibility in Parkinson's Disease (PD). The gene products, the three different paraoxonase enzymes, hydrolyze organophosphates. Three environmental factors, namely, cigarette smoking, coffee, and non-steroidal anti-inflammatory drugs (NSAID's) have shown to be inversely associated with risk of developing PD. No prior studies have evaluated Gene-Environment Interactions (GxE) between genes in the PON region and these established risk factors with PD. Further, this genetic epidemiologic project also raises questions about return of research results, particularly if evidence supports evidence for interactions between genetic variability and potentially modifiable environmental factors, such as cigarette smoking, coffee consumption and NSAID use. Methods: Case-Control Association Study was conducted using data from the NeuroGenetics Research Consortium (NGRC) which includes 2000 PD cases and 1986 unrelated controls (n= 3986). The dataset, includes genotype information for the PON locus (n= 467) and three the environmental factors (cigarette smoking, coffee, and NSAID's use). Results: No interactions were statistically significant once the Bonferroni adjustment for multiple testing was made. However, of the top hit SNP's from each of the models (smoking, coffee and NSAID's), two SNP's rs705379 (OR=1.58, 95% CI: 1.10, 2.11) and rs75071114 (OR = 0.61, 95% CI: 0.23, 1.58), are cSNP's of uncertain significance on PON2 and PON1 respectively. Conclusion: This is the first assessment of interactions between variants in the PON region and cigarette smoking, coffee, and NSAID's. While the results of this study did not provide support for statistically significant interactions, it does raise additional issues about the need for dialog by the various stakeholders to formulate policy around offering return of individual research results for findings that are of uncertain clinical significance, and possessing more personal utility than clinical.